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Diffuse Panbronchiolitis^*

A Treatable Sinobronchial Disease in Need of Recognition in the United States

^* From the Departments of Pulmonary Medicine (Drs. Krishnan and Thachil) and Radiology (Dr. Gillego), Coney Island Hospital, Brooklyn, NY.

Correspondence to: Padmanabhan Krishnan, MBBS, FCCP, Associate Director, Department of Pulmonary Medicine, Coney Island Hospital, 2601 Ocean Pkwy, Brooklyn, NY 11235

	Abstract

TOP Abstract Introduction Case Report Discussion References

 
Diffuse panbronchiolitis (DPB) is a progressive inflammatory disease, well recognized in Japan, characterized by sinusitis and obstructive small airway disease; if left untreated, it progresses to bronchiectasis, respiratory failure, and death. Treatment using low-dose erythromycin has proven to be highly efficacious. Lack of familiarity with DPB in the United States may result in the failure to correctly diagnose and treat this disorder. We describe a Cambodian man in whom the characteristic imaging and histologic features of DPB were elicited but not recognized in spite of evaluation at a referral center. When DPB was diagnosed 6 years later, he was in respiratory failure, but made an excellent recovery once erythromycin therapy was instituted. We report this case to increase physician awareness of DPB as a cause of sinobronchial disease and discuss its diagnostic features so that the disease is recognized and treated without delay.

Key Words: diffuse panbronchiolitis • long-term low-dose macrolide therapy • sinobronchial disease

	Introduction

TOP Abstract Introduction Case Report Discussion References

 
Diffuse panbronchiolitis (DPB) is an idiopathic inflammatory disease that is not uncommon in Japan, Korea, and China. It is characterized by progressive suppurative and obstructive airway disease, first involving the sinuses and respiratory bronchioles, which, left untreated, progresses to bronchiectasis, respiratory failure, and death.^{1 2 3} Its distinctive imaging and histologic features, the presence of sinusitis, and the isolation of Haemophilus influenzae and Pseudomonas aeruginosa in the sputum should enhance disease recognition.^{1 2 3} If DPB is left untreated, only 12 to 25% of patients survive 10 years.⁴ The long-term use of low-dose erythromycin therapy has proven to be highly effective in treating patients with DPB. Reported mainly among Asian patients, and primarily Japanese patients, the disease has been reported only rarely in Europe and the United States and is, therefore, unfamiliar to physicians in the West.³

This report demonstrates this fact and re-emphasizes that unless DPB is included in the differential diagnosis of sinobronchial disorders, progressive bronchiolitis, bronchiectasis, and unexplained progressive obstructive airway disease, this treatable disorder will remain underrecognized in the United States.³

	Case Report

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A 39-year-old unmarried Cambodian man complained of progressive exertional dyspnea and productive cough, which he had first noticed 10 years ago in Cambodia. These symptoms progressively worsened while in the United States, and 6 years ago he received a diagnosis of chronic interstitial pneumonitis after undergoing an open lung biopsy, which was performed at another institution. He refused lung transplantation after treatment with prednisone and azathioprine proved unsuccessful. Exertional dyspnea and productive cough worsened over the next 4 years to the point that he was dyspneic on minimal exertion when he was first seen by us.

A physical examination revealed a cachectic man who was dyspneic on minimal exertion with a cough that produced purulent sputum. Chest auscultation revealed coarse rales over both lung fields. A chest radiograph revealed small nodular shadows that were disseminated over both the mid and lower lung zones (Fig 1 ). A high-resolution CT scan (HRCT) revealed multiple bilateral centrilobular nodules that were 2 to 3 mm in size, with some having distal-branching, Y-shaped shadows that created a tree-in-bud appearance. Cystic dilatation of some nodules and areas with larger bronchiectatic cysts also were seen (Fig 2 ). These changes were similar to those seen on an HRCT that had been performed a few years earlier during investigation at the first institution. Pulmonary function testing revealed an obstructive and restrictive pattern. A sputum culture revealed the presence of H influenzae, while repeated mycobacterial cultures revealed no growth. The patient’s erythrocyte sedimentation rate and serum IgE and complement levels were normal, while serum IgG and IgA levels were mildly increased. Tests for antinuclear antibodies and cold agglutinins were negative. A sweat test was not performed. Sinus radiographs revealed pansinusitis. Blood human leukocyte antigen (HLA) typing revealed A11 and B51 antigens. A review of the open lung biopsy that had been performed earlier at the first institution revealed peribronchiolar and bronchiolar wall inflammation that was composed of lymphocytes, plasma cells, and histocytes. Intra-alveolar foamy macrophages, which have been described in DPB, were not seen.

View larger version (119K): [in this window] [in a new window] [Download PPT slide]   Figure 1.. A chest radiograph showing diffusely disseminated small nodular shadows, with unclear margins being most prominent over both lung bases.

View larger version (133K): [in this window] [in a new window] [Download PPT slide]   Figure 2.. An HRCT showing small round nodules that are distributed in centrilobular regions (posteriorly) with some nodules connected to distal-branching bronchovascular structures, providing the tree-in-bud appearance. Cystic dilatation of nodules and large cystic lesions connected to dilated proximal bronchi are also seen (anteriorly), representing areas of bronchiectasis.

View larger version (138K): [in this window] [in a new window] [Download PPT slide]   Figure 3.. An HRCT showing resolution of some of the centrilobular nodules, replacement of others by cystic bronchiolectasis, and progression of bronchiectasis.

	Discussion

TOP Abstract Introduction Case Report Discussion References

The HRCT findings coupled with the features seen on histologic examination serve best to distinguish DPB from the other better recognized sinobronchial disorders. Typical features that are seen on histologic examinations include thickening of the walls of the respiratory bronchioles, and transmural and peribronchial infiltration by lymphoctyes, plasma cells, and histocytes.

Foamy macrophages are seen in the alveoli, while the bronchial lumen contains neutrophils. Respiratory bronchiolar narrowing and ectasia of proximal terminal bronchioles occur as the disease advances.² Findings on chest radiographs include small nodular shadows over the lung bases along with areas of hyperinflation. Tramlines of bronchial dilatation are seen early in the disease process, while cystic changes of diffuse bronchiectasis are seen in more advanced disease. A grading system of these changes has been described.⁵ HRCT best delineates these changes and has been used to diagnose, stage, and assess the severity of the disease.⁶ In stage 1, small nodules, < 5 mm in diameter, are seen at the end of bronchovascular branching structures. In stage 2, these centrilobular nodules are seen connected to distal branching bronchovascular structures in a Y-shaped configuration that provides the tree-in-bud appearance. These nodules represent bronchioles filled with secretions. Cystic dilatations of these nodules representing early-stage bronchiectasis are seen in stage 3, while stage 4 is characterized by large cysts that are connected to dilated proximal bronchi. Although characteristic of DPB, these changes are not by themselves diagnostic. Similar but not identical changes have been described in patients with hypogammaglobulinemia, cystic fibrosis, primary ciliary dyskinesis, allergic bronchopulmonary aspergillosis, Wegener granulomatosis, tuberculosis, sarcoidosis, diffuse aspiration bronchiolitis, bronchiolitis obliterans, and ulcerative colitis.¹

A diagnosis of DPB is made by demonstrating its distinctive features and excluding other sinobronchial disorders. Diagnostic criteria for DPB include the following: chronic pansinusitis, chronic cough with purulent sputum, and progressive exertional dyspnea; centrilobular nodules, bronchiolar ectasia, and hyperinflation seen on HRCT; an obstructive or mixed obstructive restrictive pattern on pulmonary function tests; and transmural and peribronchiolar infiltration with lymphocytes and plasma cells seen in lung biopsy specimens. Additional features that are seen in many patients include increased serum cold agglutinins and rheumatoid factor titers, increased serum IgA and IgG levels, sputum cultures that are positive for H influenzae and P aeruginosa, and HLA Bw54 antigen in blood.^{1 2 3} A lung biopsy is usually not necessary in countries where the disease is of high prevalence.³ Even in North America, the clinical radiographic and CT scan features may be distinctive enough to allow for a presumptive diagnosis of DPB and initiation of erythromycin therapy. This approach is valid when other causes of sinopulmonary disease, bronchiolitis, nodular lung disease, and bronchiectasis have been excluded clinically.^{1 2 3}

Prior to the discovery of the beneficial effect of erythromycin therapy, the prognosis for patients with DPB was poor, with 5-year and 10-year survival rates of 42% and 25.4%, respectively.⁴ Since then, many studies have established the efficacy of erythromycin therapy in improving symptoms, lung function, CT scan changes, and survival rates.^{7 8} In patients with P aeruginosa that is isolated in the sputum, erythromycin therapy improved the 10-year survival from 12.4 to > 90%.⁹ Other members of the macrolide family also have been found to be as efficacious in treating patient’s with DPB.¹ The duration of treatment remains unclear, but most patients in Asia have been treated for > 2 years. A logical point at which to stop therapy is on the resolution of symptoms and the disappearance of centrilobular nodules from the HRCT.¹ Once treatment is stopped, the patient must be followed up for relapse by symptoms and HRCT, as recurrence has been documented even after lung transplantation.¹⁰ The beneficial effect of erythromycin therapy is not antibacterial, as macrolide levels in the airways of patients with DPB are well below the minimal level to inhibit the concentration of H influenzae and P aeruginosa.⁸ An immune system modulating effect is more likely, as demonstrated by the ability of erythromycin to reduce neutrophil influx by decreasing levels of interleukins that are chemoattractants.⁸

While only a few cases of DPB have so far have been reported in the United States, increased physician awareness of this disorder will likely lead to an increase in the number of cases.³ Health-care professionals in North America, especially pulmonologists, radiologists, and pathologists, must be familiar with the features of this disease as timely recognition will ensure that patients do not miss the opportunity to receive efficacious macrolide therapy.

	Footnotes

 
Abbreviations: DPB = diffuse panbronchiolitis; HLA = human leukocyte antigen; HRCT = high-resolution CT

Received for publication April 10, 2001. Accepted for publication July 25, 2001.

	References

TOP Abstract Introduction Case Report Discussion References

 

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3. Fitzgerald, JE, King, TE, Lynch, DA, et al (1996) Diffuse panbronchiolitis in the United States. Am J Respir Crit Care Med 154,497-503[Abstract]
4. Nakada, K, Inatomi, K (1981) Progress, treatment: annual report on the study of diffuse interstitial lung disease; grant information. ,21 Ministry of Health and Welfare of Japan Tokyo, Japan.
5. Nakata, K, Tanimoto, M (1981) Diffuse panbronchiolitis. Rinsho Hoshasen 26,1133-1142[Medline]
6. Akira, M, Kitatani, F, Yong, J, Sik, L, et al (1988) Diffuse panbronchiolitis: evaluation with high resolution CT. Radiology 168,433-438,[Abstract/Free Full Text]
7. Kudoh, S, Uteka, T, Hagiwara, K, et al (1987) Clinical effects of low dose long term erythromycin chemotherapy of diffuse panbronchiolits. Nihon Kyobu Shikkan Gakkai Zasshi 25,632-642[Medline]
8. Nagai, H, Shishido, H, Yoneda, R, et al (1995) Long-term low-dose administration of erythromycin to patients with diffuse panbronchiolitis. Respiration 58,145-149
9. Fuji, T, Kadota, JI, Irda, KK, et al (1995) Long term effect of erythromycin therapy in patients with chronic pseudomonas aeruginosa infection. Thorax 50,1246-1252[Abstract]
10. Bas, MA, Kussin, PS, Van Trigt, P, et al (1995) Recurrence of diffuse panbronchiolitis after lung transplantation. Am J Respir Crit Care Med 151,895-898[Abstract]

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